Human immunodeficiency virus (HIV) is a lentivirus that infects and destroys CD4-bearing lymphocytes1,2, eventually rendering the host's immune system incapable of mounting sufficient responses to even commonly- innocuous pathogens1,3,4. HIV was first discovered in the 1980s predominantly among gay men in San Francisco and New York1,5,6, but since then has developed into a world-wide epidemic, with 70% of the 35 million individuals currently infected with HIV living in the developing world1,4,7. t was quickly noted however that humans contain natural variation in their response to HIV; some individuals never become infected with HIV, while others upon infection never develop Acquired Immunodeficiency Syndrome (AIDS), among other variable responses1,8. Researchers have since believed that the underlying genetic variation present among human populations may be partially responsible for these differences in human response to HIV, thus representing a possible way to develop a treatment for HIV. However, despite 20+ years of human genetics research, including candidate gene studies in the 1990s and genome-wide association studies (GWAS) in the late 2000s, there is still no vaccine for HIV1,9 and very few genetic loci that have been identified as significantly associated with HIV-related phenotypes8,10-13. Possible explanations for this lack of progress is that the most recent set of studies, GWAS, interrogated the entire genome for association in a hypothesis-free approach, thus producing a large multiple-testing burden and giving little insight into which loci are most important. Additionally, GWAS only focused on common genetic variation (minor allele frequency, MAF, >5%), whereas it is known that much genetic variation is present at MAFs below 5%8. Therefore, the aims of this proposal are focused on overcoming these drawbacks of the GWAS approach. First, AIM 1 will be to identify candidate human HIV-target genes with an excess of rare variation in association with either HIV-infection or AIDS- progression. A list of 1,693 HIV-candidate genes with strong a priori biological evidence has already been created and by conducting gene-exome sequencing we will discover rare variants; taken together these steps will allow us to overcome the issues of lacking a hypothesis, containing a large multiple-testing burden and being limited to common variation. Second, AIM 2 will be to validate the top 25 hits from AIM 1 by a combination of follow-up genoptying/sequencing in multiple cohorts and in vitro molecular assays, including siRNA knockdowns and CRISPRs. By conducting these experiments we will provide more rigorous evidence for the associations discovered in AIM 1 as well as begin the process of understanding new host-biology relevant to human response to HIV and relevant to potential drug targets and vaccine development.